CN113956159A - Preparation method of difluoro three-membered ring compound - Google Patents
Preparation method of difluoro three-membered ring compound Download PDFInfo
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- CN113956159A CN113956159A CN202111163314.XA CN202111163314A CN113956159A CN 113956159 A CN113956159 A CN 113956159A CN 202111163314 A CN202111163314 A CN 202111163314A CN 113956159 A CN113956159 A CN 113956159A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 27
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 197
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims abstract description 116
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 76
- 235000009518 sodium iodide Nutrition 0.000 claims abstract description 38
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 15
- -1 olefin compound Chemical class 0.000 claims abstract description 11
- 238000010189 synthetic method Methods 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000011261 inert gas Substances 0.000 claims abstract description 7
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 68
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- CSSYKHYGURSRAZ-UHFFFAOYSA-N methyl 2,2-difluoroacetate Chemical compound COC(=O)C(F)F CSSYKHYGURSRAZ-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 40
- 238000001308 synthesis method Methods 0.000 abstract description 7
- 230000003321 amplification Effects 0.000 abstract description 3
- 238000012840 feeding operation Methods 0.000 abstract description 3
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 62
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
- 239000012043 crude product Substances 0.000 description 31
- 239000003208 petroleum Substances 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- GQJCAQADCPTHKN-UHFFFAOYSA-N methyl 2,2-difluoro-2-fluorosulfonylacetate Chemical compound COC(=O)C(F)(F)S(F)(=O)=O GQJCAQADCPTHKN-UHFFFAOYSA-N 0.000 description 30
- 238000004440 column chromatography Methods 0.000 description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000000047 product Substances 0.000 description 5
- OYEXEQFKIPJKJK-UHFFFAOYSA-N 2-(cyclohexen-1-yl)acetonitrile Chemical compound N#CCC1=CCCCC1 OYEXEQFKIPJKJK-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- PXTONRTYYUAUJU-UHFFFAOYSA-N tert-butyl 3-methylidenepyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=C)C1 PXTONRTYYUAUJU-UHFFFAOYSA-N 0.000 description 2
- SSZOCHFYWWVSAI-UHFFFAOYSA-N 1-bromo-2-ethenylbenzene Chemical compound BrC1=CC=CC=C1C=C SSZOCHFYWWVSAI-UHFFFAOYSA-N 0.000 description 1
- WGGLDBIZIQMEGH-UHFFFAOYSA-N 1-bromo-4-ethenylbenzene Chemical compound BrC1=CC=C(C=C)C=C1 WGGLDBIZIQMEGH-UHFFFAOYSA-N 0.000 description 1
- ZRWMAMOBIQQJSA-UHFFFAOYSA-N 3-methylidenecyclobutane-1-carbonitrile Chemical compound C=C1CC(C#N)C1 ZRWMAMOBIQQJSA-UHFFFAOYSA-N 0.000 description 1
- RMGBWPMWUZSIMH-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C(=C)C1=CC=CC=C1 RMGBWPMWUZSIMH-UHFFFAOYSA-N 0.000 description 1
- IRQWEODKXLDORP-UHFFFAOYSA-N 4-ethenylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=C)C=C1 IRQWEODKXLDORP-UHFFFAOYSA-N 0.000 description 1
- DXPPIEDUBFUSEZ-UHFFFAOYSA-N 6-methylheptyl prop-2-enoate Chemical compound CC(C)CCCCCOC(=O)C=C DXPPIEDUBFUSEZ-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- IHOVFYSQUDPMCN-DBEBIPAYSA-N chembl444172 Chemical compound C([C@H](COC=1C2=CC=CN=C2C=CC=1)O)N(CC1)CCN1[C@@H]1C2=CC=CC=C2[C@H]2C(F)(F)[C@H]2C2=CC=CC=C12 IHOVFYSQUDPMCN-DBEBIPAYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- YOIVHDQJCFLRRB-BQYQJAHWSA-N ethyl (e)-3-(2-fluorophenyl)prop-2-enoate Chemical compound CCOC(=O)\C=C\C1=CC=CC=C1F YOIVHDQJCFLRRB-BQYQJAHWSA-N 0.000 description 1
- YOOKYIPLSLPRTC-VMPITWQZSA-N ethyl (e)-3-(4-bromophenyl)prop-2-enoate Chemical compound CCOC(=O)\C=C\C1=CC=C(Br)C=C1 YOOKYIPLSLPRTC-VMPITWQZSA-N 0.000 description 1
- PXRBXTMPZDXIML-UHFFFAOYSA-N ethyl 2-(2,6-dimethoxyphenyl)prop-2-enoate Chemical compound CCOC(=O)C(=C)C1=C(OC)C=CC=C1OC PXRBXTMPZDXIML-UHFFFAOYSA-N 0.000 description 1
- QARHTDLVHYQXRK-UHFFFAOYSA-N ethyl 2-(4-methylphenyl)prop-2-enoate Chemical compound CCOC(=O)C(=C)C1=CC=C(C)C=C1 QARHTDLVHYQXRK-UHFFFAOYSA-N 0.000 description 1
- DHNGCHLFKUPGPX-RMKNXTFCSA-N ethyl trans-p-methoxycinnamate Chemical compound CCOC(=O)\C=C\C1=CC=C(OC)C=C1 DHNGCHLFKUPGPX-RMKNXTFCSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- OSWTXCSCDKIANQ-UHFFFAOYSA-N methyl 3-methylidenecyclobutane-1-carboxylate Chemical compound COC(=O)C1CC(=C)C1 OSWTXCSCDKIANQ-UHFFFAOYSA-N 0.000 description 1
- NUMHUJZXKZKUBN-UHFFFAOYSA-N methyl 4-ethenylbenzoate Chemical compound COC(=O)C1=CC=C(C=C)C=C1 NUMHUJZXKZKUBN-UHFFFAOYSA-N 0.000 description 1
- CEOILRYKIJRPBZ-UHFFFAOYSA-N methyl cyclopent-3-ene-1-carboxylate Chemical compound COC(=O)C1CC=CC1 CEOILRYKIJRPBZ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- MECAHFSQQZQZOI-UHFFFAOYSA-N tert-butyl 3-methylideneazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=C)C1 MECAHFSQQZQZOI-UHFFFAOYSA-N 0.000 description 1
- PDTZMULNKGUIEJ-UHFFFAOYSA-N tert-butyl 4-methylidenepiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=C)CC1 PDTZMULNKGUIEJ-UHFFFAOYSA-N 0.000 description 1
- QPKZZWRUFCUFEI-UHFFFAOYSA-N tert-butyl n-cyclopent-3-en-1-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CC=CC1 QPKZZWRUFCUFEI-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229950005752 zosuquidar Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/12—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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Abstract
The invention discloses a synthesis method of a difluoro three-membered ring compound, which takes an olefin compound and excessive fluoro sulfonyl methyl difluoroacetate as raw materials, takes methylbenzene, THF or dioxane as a solvent, and is added with sodium iodide and trimethylchlorosilane to prepare the difluoro three-membered ring compound under the protection of inert gas. The synthetic method of the difluoro tricyclic compound is more convenient, the feeding operation of the reaction is simple and convenient, the application range is wider, the reaction condition is mild, and the method is more suitable for process amplification.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a preparation method of a difluoro three-membered ring compound.
Background
Modern pharmaceutical chemistry makes extensive use of two structural topics to improve the physicochemical characteristics of compounds: the fluorine atom and the small ring, namely the difluoro three-membered ring have the two properties, so the fluorine atom and the small ring are regarded as structural fragments with great prospect in the early drug discovery. The most prominent example of this is the experimental anti-tumor drug zosuquidar, which has reached three clinical trials. The following synthetic methods are described in Transition Metal-free gel-difiuoro-hydrolysis of olefins with CF3SiMe3-NaI System: a Recipe for Electron-purification Substrates, by way of example, Pavel S.Nosik et al:
the practical application has two disadvantages that 1. the CF in the reactant is added by adopting the principle of slow dripping3SiMe3The mixture needs to be slowly added into the reaction (generally, the dropwise addition is needed for 12 to 16 hours); 2. with electron-withdrawing groups present in the substrate (carboxyl, nitro, cyano)This method is not generally applicable. Due to these two limitations, it is necessary to develop a synthetic method with simple operation and wider applicability.
Disclosure of Invention
The invention aims to solve the problems, provides a preparation method of a difluoro tricyclic compound, solves the problems of complicated reaction operation and small application range of the existing synthetic method, is simple and convenient in feeding operation of the reaction, has wider application range than the traditional synthetic method, is mild in reaction conditions, and is more suitable for process amplification.
The purpose of the invention is realized as follows:
the synthesis method of the difluoro three-membered ring compound takes an olefin compound and excessive fluoro sulfonyl methyl difluoroacetate as raw materials, takes toluene, dioxane or tetrahydrofuran as solvents, and is prepared by adding sodium iodide and trimethyl chlorosilane under the protection of inert gas.
The synthesis reaction formula in the synthesis method of the difluoro three-membered ring compound is as follows:
the synthesis reaction temperature of the synthesis method of the difluoro three-membered ring compound is 80-120 ℃, and the synthesis reaction time is 5-16 hours.
The inert gas in the synthesis method of the difluoro three-membered ring compound is selected to be nitrogen.
The synthesis method of the difluoro three-membered ring compound also comprises the step of separating and purifying the product by a column.
In the method for synthesizing the difluoro tricyclic compound, the dosage of the olefin compound is 1 eq; the dosage of the fluosulfonyl difluoroacetic acid methyl ester is 1.2 to 3 eq; the amounts of sodium iodide and chlorotrimethylsilane used were 2.0 eq.
The structural formula of the difluoro three-membered ring compound in the synthesis method of the difluoro three-membered ring compound is as follows:
the synthetic method of the difluoro tricyclic compound is more convenient, the feeding operation of the reaction is simple and convenient, the application range is wider, the reaction condition is mild, and the method is more suitable for process amplification.
Detailed Description
The present invention will be further described with reference to the following examples.
The invention discloses a synthetic method of a difluoro three-membered ring compound,
using an olefin compound and excessive fluorosulfonyl methyl difluoroacetate as raw materials, using toluene, tetrahydrofuran or dioxane as a solvent, adding sodium iodide and trimethylchlorosilane, heating to 80-120 ℃ under the protection of inert gas for reacting for 5-16 hours, passing the product through a column, and separating and purifying to obtain the product;
the synthesis reaction formula is as follows:
the dosage of the fluosulfonyl difluoroacetic acid methyl ester is 1.2 to 3 eq;
the amounts of sodium iodide and chlorotrimethylsilane were 2.0 eq;
the products prepared using the process of the invention were as follows:
wherein the inert gas is selected to be nitrogen.
Example 1:
ethyl 3- (4-methoxyphenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to give sample 1, the product of example 1.
Sample 1 yield 50%.
1H-NMR(CDCl3,400MHz)δ7.16(d,2H),5.87(d,2H),4.25(q,2H),3.79(S,3H)3.43(q,1H),2.63(q,1H),1.31(t,3H).
Example 2
Ethyl 3- (4-bromophenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by passing through a petroleum ether column to obtain sample 2 of example 2, sample 2 having the following structural formula:
the yield of sample 2 was 46%.
1H-NMR(CDCl3,400MHz)δ7.48(d,2H),7.12(d,2H),4.26(q,2H),3.41(q,1H),2.68(q,1H),1.32(t,3H).
Example 3
Ethyl 3- (3, 4-dimethylphenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 3 of example 3, sample 3 having the following structural formula:
the yield of sample 3 was 46%.
1H-NMR(CDCl3,400MHz)δ7.25(s,1H),7.01(s,1H),4.25(q,2H),3.45-3.40(m,1H),2.70-2.65(m,1H),2.30(s,1H),2.25(s,6H),1.31(t,3H).
Example 4
4-vinylbenzoic acid (1.0eq), methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 4 of example 4, sample 4 having the following structural formula:
the yield of sample 4 was 70%.
1H-NMR(CDCl3,400MHz)δ8.07(d,1H),7.33(d,1H),2.81(q,2H),1.95-1.87(m,1H),1.74-1.69(m,1H).
Example 5
1-bromo-4-vinylbenzene (1.0eq), methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 5 of example 5, sample 5 having the following structural formula:
the yield of sample 5 was 80%.
1H-NMR(DMSO-d6,400MHz)δ7.49-7.45(m,1H),7.32-7.28(m,2H),3.07-2.99(m,1H),2.05-1.95(m,2H).
Example 6
Ethyl 3- (2-fluorophenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added to react at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 6 of example 6, sample 6 having the following structural formula:
the yield of sample 6 was 40%.
1H-NMR(CDCl3,400MHz)δ7.33-7.01(m,3H),4.27(t,2H),3.56(t,1H),3.12(q,1H),1.33(t,3H).
Example 7
The cyclohexylidene ethyl acetate (1.0eq) and the fluorosulfonyl methyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added to react at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to give sample 7 of example 7, sample 7 having the following structural formula:
the yield of sample 7 was 40%.
1H-NMR(CDCl3,400MHz)δ7.33-7.01(m,3H),4.27(t,2H),3.56(t,1H),3.12(q,1H),1.33(t,3H).
Example 8
Ethyl 2- (4-propylphenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 8 of example 8, sample 8 having the following structural formula:
the yield of sample 8 was 70%.
1H-NMR(CD4O,400MHz)δ7.29(d,2H),7.16(d,2H),4.27(t,2H),2.58(t,2H),2.53-2.48(m,1H),1.99-1.93(m,1H),1.68-1.59(m,2H)，0.94(t,3H).
Example 9
1-bromo-2-vinylbenzene (1.0eq), methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 9 of example 9, sample 9 having the following structural formula:
sample 9 yield was 85%.
1H-NMR(CDCl3,400MHz)δ7.60(d,1H),7.31-7.14(m,3H),2.92-2.84(m,1H),1.93-1.84(m,1H),1.74-1.84(m,1H).
Example 10
Dissolving ethyl 2- ([1,1' -biphenyl ] -4-yl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) in toluene, adding sodium iodide (2eq) and trimethylchlorosilane (2eq), and reacting at 80 ℃ for 5 hours under the protection of nitrogen. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by passing through a petroleum ether column to obtain sample 10 of example 10, sample 10 having the following structural formula:
sample 10 yield was 90%.
1H-NMR(CDCl3,400MHz)δ7.60(d,3H),7.48-7.43(m,4H),7.31-7.24(m,1H),4.25-4.15(m,2H),2.65(s,1H),1.96(s,1H),1.23(t,3H).
Example 11
Ethyl 2- (m-tolyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added to react at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 11 of example 11, sample 11 having the following structural formula:
sample 11 yield was 88%.
1H-NMR(CDCl3,400MHz)δ7.60(d,3H),7.48-7.43(m,4H),7.31-7.24(m,1H),4.25-4.15(m,2H),2.65(s,1H),1.96(s,1H),1.23(t,3H).
Example 12
Methyl 4-vinylbenzoate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and chlorotrimethylsilane (2eq) were added to react at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 12 of example 12, sample 12 having the following structural formula:
the yield of sample 12 was 88%.
1H-NMR(CDCl3,400MHz)δ8.00(d,2H),7.28(d,2H),3.91(s,3H),2.78(q,1H),1.94-1.84(m,1H),1.72-1.64(m,1H).
Example 13
Isooctyl acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by passing through a petroleum ether column to obtain sample 13 of example 13, and sample 13 had the following structural formula:
the yield of sample 13 was 50%.
1H-NMR(CDCl3,400MHz)δ4.07(d,2H),2.43(q,1H),2.04(q,1H),1.74(q,1H),1.59(s,2H),1.40-1.29(m,6H),1.89(s,6H).
Example 14
Ethyl 2- (4-isopropoxyphenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 14 of example 14, sample 14 having the following structural formula:
sample 14 yield was 90%.
1H-NMR(CDCl3,400MHz)δ7.50(d,2H),6.86(d,2H),4.69(q,1H),4.21(q,1H),1.96(s,1H),1.23(t,9H).
Example 15
Dissolving ethyl 2- ([1,1' -biphenyl ] -3-yl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) in toluene, adding sodium iodide (2eq) and trimethylchlorosilane (2eq), and reacting at 80 ℃ for 5 hours under the protection of nitrogen. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 15 of example 15, sample 15 having the following structural formula:
sample 15 yield was 90%.
1H-NMR(DMSO-d6,400MHz)δ7.68-7.65(m,4H),7.47(q,3H),7.39(q,2H),4.18-4.07(m,2H),2.65-2.59(m,1H),2.46-2.43(m,9H)，1.14(t,3H).
Example 16
Ethyl 2- (2, 6-dimethoxyphenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 16 of example 16, sample 16 having the following structural formula:
the yield of sample 16 was 90%.
1H-NMR(CDCl3,400MHz)δ7.26(t,1H),6.57(d,2H),4.23-4.05(m,2H),3.82(s,6H),2.70-2.63(m,1H),1.86-1.80(m,1H)，1.17(t,3H).
Example 17
Dissolving ethyl 2- ([1,1' -biphenyl ] -2-yl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) in toluene, adding sodium iodide (2eq) and trimethylchlorosilane (2eq), and reacting at 80 ℃ for 5 hours under the protection of nitrogen. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 17 of example 17, sample 17 having the following structural formula:
sample 17 yield was 90%.
1H-NMR(DMSO-d6,400MHz)δ7.68-7.65(m,4H),7.47(q,3H),7.39(q,2H),4.18-4.07(m,2H),2.65-2.59(m,1H),2.46-2.43(m,9H)，1.14(t,3H).
Example 18
Ethyl 2- (4-isopropylphenyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to give sample 18 of example 18, sample 18 having the following structural formula:
the yield of sample 18 was 90%.
1H-NMR(CD4O,400MHz)δ7.27(q,4H),4.19-4.07(m,2H),2.93(q,1H),2.64-2.58(m,1H),2.03-1.96(m,1H)，1.24(d,6h),1.18(t,3H).
Example 19
Ethyl 2- (p-tolyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to give sample 19 of example 19, sample 19 having the following structural formula:
sample 19 yield was 91%.
1H-NMR(CD4O,400MHz)δ7.21-7.14(m,4H),4.21-4.01(m,2H),3.09-3.02(m,1H),2.33(s,3H),1.99-1.91(m,1H)，1.60(t,3H).
Example 20
Ethyl 2- (o-tolyl) acrylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added to react at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 20 of example 20, sample 20 having the following structural formula:
sample 20 yield was 91%.
1H-NMR(CD4O,400MHz)δ7.21-7.14(m,4H),4.21-4.01(m,2H),3.09-3.02(m,1H),2.33(s,3H),1.99-1.91(m,1H)，1.60(t,3H).
Example 21
N-Boc-4-methylenepiperidine (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added to react at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by passing through a petroleum ether column to obtain sample 21 of example 21, and the structural formula of sample 21 was as follows:
the yield of sample 21 was 33%.
1H-NMR(CDCl3,400MHz)δ7.30–7.22(m,1H),2.07–1.88(m,2H),1.78–1.52(m,3H),1.51–1.37(m,10H),1.37–1.16(m,3H),1.09–0.93(m,2H).
Example 22
1-Boc-3-methylenepyrrolidine (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to give sample 22 of example 22, sample 22 having the following structural formula:
the yield of sample 22 was 94%.
1H-NMR(CDCl3,400MHz)δ3.62–3.26(m,4H),2.15–2.02(m,1H),1.93(s,1H),1.46(s,9H),1.41–1.28(m,2H).
Example 23
1-Boc-3-methylene azetidine (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 23 of example 23, sample 23 having the following structural formula:
sample 23 yield was 56%.
1H NMR(CD4O,400MHz)δ4.37–4.27(m,2H),4.18(d,2H),3.36–3.26(m,1H),1.73(t,2H).
Example 24
1-Boc-3-methylenepyrrolidine (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 24 of example 24, sample 24 having the following structural formula:
the yield of sample 24 was 84%.
1H-NMR(CD4O，400MHz)δ3.54(m,1H),3.50–3.34(m,3H),3.31(s,1H),2.30(m,1H),2.14(m,1H),1.72–1.59(m,2H).
Example 25
3-cyclopentene-1-carboxylic acid methyl ester (1.0eq), fluorosulfonyl difluoroacetic acid methyl ester (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 25 of example 25, sample 25 having the following structural formula:
sample 25 yield was 43%.
1H-NMR(CDCl3，400MHz)δ3.25–2.81(m,1H),2.49–2.17(m,4H),2.10–1.97(m,2H).
Example 26
1-cyclohexene acetonitrile (1.0eq), methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 26 of example 26, sample 26 having the following structural formula:
the yield of sample 26 was 45%.
1H-NMR(CDCl3,400MHz)δ2.48(q，2H),1.96-1.86(m,2H),1.79-1.67(m,2H),1.46-1.26(m,5H).
Example 27
1- (N-Boc-amino) -3-cyclopentene (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 27 of example 27, sample 27 having the following structural formula:
the yield of sample 27 was 41%.
1H-NMR(CDCl3,400MHz)δ4.44(s,1H),4.04(s,1H),2.40-2.35(m,2H),1.97-1.93(m,2H),1.43(s,9H).
Example 28
3-methylenecyclobutylcarbonitrile (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added thereto, followed by reaction at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by passing through a petroleum ether column to obtain sample 28 of example 28, sample 28 having the following structural formula:
sample 28 yield was 49%.
1H-NMR(CDCl3,400MHz)δ3.27-3.18(m,1H),2.67(t,2H),2.61-2.54(m,2H),1.31(t,2H).
Example 29
1-phenyl vinyl boronic acid pinacol ester (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added to react at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 29 of example 29, sample 29 having the following structural formula:
the yield of sample 29 was 15%.
1H-NMR(CDCl3,400MHz)δ7.33-7.22(m,5H),2.09-2.04(m,1H),1.72-1.63(m,1H),1.24(s,6H),1.20(s,6H).
Example 30
Methyl 3-methylenecyclobutanecarboxylate (1.0eq) and methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by passing through a petroleum ether column to obtain sample 30 of example 30, wherein sample 30 has the following structural formula:
the yield of sample 30 was 25%.
1H-NMR(CDCl3,400MHz)δ3.32-3.24(m,1H),2.58-2.46(m,4H),1.24(t,2H).
Example 31
1-cyclohexene acetonitrile (1.0eq), methyl fluorosulfonyl difluoroacetate (1.2eq) were dissolved in toluene, and sodium iodide (2eq) and trimethylchlorosilane (2eq) were added and reacted at 80 ℃ for 5 hours under nitrogen protection. The reaction was cooled, water was added, and the toluene layer was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether to obtain sample 31 of example 31, sample 31 having the following structural formula:
the yield of sample 31 was 23%.
1H-NMR(DMSO-d6,400MHz)δ2.60(t,2H),1.77-1.72(m,1H),1.61-1.54(m,3H),1.50-1.39(m,3H),1.34-1.16(m,6H).
The above embodiments are provided only for illustrating the present invention and not for limiting the present invention, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention, and therefore all equivalent technical solutions should also fall within the scope of the present invention, and should be defined by the claims.
Claims (7)
1. A synthetic method of a difluoro three-membered ring compound is characterized in that an olefin compound and excessive fluoro sulfonyl methyl difluoroacetate are used as raw materials, toluene, dioxane or tetrahydrofuran are used as solvents, sodium iodide and trimethylchlorosilane are added, and the preparation is carried out under the protection of inert gas.
2. The method of synthesizing a difluorotricyclic compound according to claim 1, wherein the synthesis reaction formula is as follows:
3. the method for synthesizing a difluorotricyclic compound according to claim 1, wherein the synthesis reaction temperature is 80 ℃ and the synthesis reaction time is 5 to 16 hours.
4. The method for synthesizing a difluorothree-membered ring compound according to claim 1, wherein the inert gas is nitrogen.
5. The method of synthesizing a difluoro three-membered ring compound according to claim 1, wherein said method further comprises subjecting the product to column separation and purification.
6. The method for synthesizing a difluorotricyclic compound according to claim 1, wherein the amount of said olefinic compound is 1 eq; the dosage of the fluosulfonyl difluoroacetic acid methyl ester is 1.2 to 3 eq; the amounts of sodium iodide and chlorotrimethylsilane were 2.0 eq.
7. The method for synthesizing a difluorotricyclic compound according to any one of claims 1 to 5, wherein the difluorotricyclic compound has the following structural formula:
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